tbuckley/cabot-search huggingface dataset:
NIMG-22. AN AI-BASED COORDINATE SYSTEM ELUCIDATES RADIOGENOMIC HETEROGENEITY OF GLIOBLASTOMA VIA DEEP LEARNING AND MANIFOLD EMBEDDINGS
Authors: Fanyang Yu, Anahita Fathi Kazerooni, Erik Toorens, Hamed Akbari, Chiharu Sako, Elizabeth Mamourian, Stephen Bagley, Zev A Binder, Robert A Lustig, Steven Brem, Donald M O’Rourke, Tapan Ganguly, Spyridon Bakas, MacLean Nasrallah, Pratik Chaudhari, Christos Davatzikos
Journal: Neuro-Oncology (2022)

Abstract PURPOSE There is evidence that molecular heterogeneity of glioblastoma is associated with heterogeneity of MR imaging signatures. Modern machine learning models, such as deep neural networks, provide a tool for capturing such complex relationships in high-dimensional datasets. This study leverages recent advances in visualizing neural networks to construct a radiogenomics coordinate system whose axes reflect the expression of imaging signatures of genetic mutations commonly found in glioblastoma. METHODS Multi-parametric MRI (mpMRI) scans (T1, T1-Gd, T2, T2-FLAIR, DSC, DTI) of 254 subjects with glioblastoma were retrospectively collected. Radiomics features, including histograms, morphologic and textural descriptors, were derived. Genetic markers were obtained through next generation sequencing (NGS) panel. A multi-label classification deep neural network was trained for predicting mutation status in key driver genes, EGFR, PTEN, NF1, TP53 and RB1. We utilized a nonlinear manifold learning method called Intensive Principal Component Analysis (InPCA), to visualize the output probability distributions from the trained model. The first three principal components (PCs) were selected for constructing the coordinate system. RESULTS The axes derived from InPCA analysis were associated with molecular pathways known to be implicated in glioblastoma: (1) Increasing values of PC1 were associated with primary involvement of P53 then RB1 then MAPK then RTK/PI3K; (2) Increasing values of PC2 were associated with primary involvement of RTK then RB1/P53/MAPK then PI3K; (3) Increasing values of PC3 were associated with primary involvement of MAPK then RB1/P53/RTK/PI3K. Imaging features significantly associated with each of three PCs (p&amp;lt; 0.05) were identified by Pearson correlation analysis. CONCLUSION Deep learning followed by nonlinear manifold embedding identifies a radiogenomics coordinate system spanned by three components which were associated with different molecular pathways of glioblastoma. The heterogeneity of radiogenomic signatures captured by this coordinate system offers in vivo biomarkers of the molecular heterogeneity of glioblastoma.
DDEL-07. DETERMINATION OF TOTAL AND UNBOUND LEVELS OF A POTENT INHIBITOR OF POLY ADP-RIBOSE POLYMERASE, NIRAPARIB, IN HUMAN PLASMA, CEREBROSPINAL FLUID AND BRAIN TUMOR BY A VALIDATED LC-MS/MS ASSAY
Authors: William Knight, Tigran Margaryan, Nader Sanai, Artak Tovmasyan
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Niraparib is an orally available inhibitor of poly ADP-ribose polymerase with high selectivity for PARP1 and PARP2. It is currently approved in the United States for the treatment of ovarian, fallopian tube, and primary peritoneal cancer. Herein we present the development and validation of an LC-MS/MS method for determination of total and unbound levels of niraparib in human plasma, cerebrospinal fluid (CSF) and glioblastoma tissue. METHODS Niraparib was extracted from human plasma, CSF and glioblastoma homogenate samples by protein precipitation with methanol. Unbound fractions of niraparib in plasma and brain tissues were determined by equilibrium dialysis. Validation was performed using Sciex ExionLC UHPLC system coupled with Sciex QTRAP 6500+ MS/MS detector using positive electrospray ionization mode. The method was validated according to FDA guidelines and CAP/CLIA regulations. RESULTS The method was validated for 1-10,000 nmol/L concentration range using plasma as matrix for all biospecimens. The chromatographic separation was performed on Phenomenex Kinetex™ PS C18 column with total run time of 3.5 min with gradient elution. Maximum coefficient of variation for intra- and inter-day precision was 10.6% and the accuracy was within 92.8-118.5% in all matrices. The analyte is stable in plasma and brain homogenate for at least 6 hours at room temperature (RT) and at least 32 days at -20°C. Stability of stock and working solutions was demonstrated for at least 21 hours (RT) and 41 days (4°C). The fraction unbound of niraparib in human plasma and brain were determined to be 0.15 and 0.05, respectively. CONCLUSIONS A sensitive and rapid bioanalytical method is developed and validated to quantify total and unbound niraparib levels in human plasma, CSF and glioblastoma tissue. This method is currently employed to assess plasma pharmacokinetics and CNS penetration of niraparib in newly-diagnosed glioblastoma and recurrent IDH1/2(+) ATRX mutant glioma patients (NCT05076513).
BIOM-02. MUTATIONAL ANALYSIS AND SINGLE CELL SEQUENCING OF MELANOMA BRAIN METASTASES REVEALS BRAF STATUS CORRELATES WITH CLINICAL OUTCOME AND DIFFERENTIAL IMMUNE POPULATIONS
Authors: Harish Vasudevan, Cyrille Delley, Alexander Aabedi, Poojan Shukla, Minh Nguyen, Ramin A Morshed, Jacob S Young, Ben Demaree, Devan Diwanji, Shawn L Hervey-Jumper, Lauren Boreta, Shannon Fogh, Jean Nakamura, Philip Theodospoulos, Joanna J Phillips, Mariza Daras, Katy Tsai, Penny Sneed, Manish Aghi, David Raleigh, Steve Braunstein, Adam Abate
Journal: Neuro-Oncology (2022)

Abstract Understanding the molecular landscape and microenvironment of melanoma brain metastases is critical to devise improved treatments. Here, we perform bulk and single cell genomic analysis of melanoma brain metastases to identify molecular correlates of clinical outcome. 84 consecutive patients who underwent surgical resection at a single institution with a histo-pathologically confirmed diagnosis of melanoma brain metastasis were retrospectively identified. In 60 patients (71%) with sufficient brain metastasis tissue for targeted next generation sequencing, DNA mutations were assessed with a CLIA certified sequencing assay. Single nuclear RNA sequencing using the 10x platform was performed on n=6 samples from treatment naïve patients. Overall survival (OS) and CNS progression free survival (CNS PFS) from time of brain metastasis diagnosis were estimated using the Kaplan-Meier method. The median patient age was 62 years old (range: 25-78 years), and the median clinical follow up was 17 months. A total of 33 patients (39%) had BRAFV600E melanoma brain metastases. Multivariate analysis incorporating age, performance status, and extracranial disease revealed BRAF status was an independent prognostic factor for OS (p&amp;lt; 0.05). In patients undergoing targeted next generation sequencing, the most common pathogenic variant was TERT promoter mutation (n=44; 73%). With regard to TCGA molecular melanoma subgroups, NRAS mutant (n=22; 37%) brain metastases were most common followed by BRAF mutant (n=20; 33%), NF1 mutant (n=11; 18%), and triple wildtype (n=7; 12%). Evaluation of clinical outcomes in the context of next generation sequencing results revealed no differences by TERT status but demonstrated worse overall survival in the BRAF mutant molecular group (p&amp;lt; 0.01, log-rank test). Single nuclear sequencing of 36,115 nuclei across 6 samples revealed BRAF wildtype tumors exhibit greater infiltrating immune cell populations including microglia and T cell subtypes. Future work will require integration of these findings with different systemic therapy regimens and across larger, prospective, multi-institutional cohorts.
DISP-03. FEMALE-SPECIFIC CANCER METASTASES TO THE BRAIN: OUTCOMES IN A MEDICALLY UNDERSERVED AREA
Authors: Annabelle Shaffer, David Krist, Emily Smith, Anant Naik, Anisha Mittal, Alexander Smith, Mika Janbahan, Daniel Najafali, Wael Hassaneen
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Cancer care in medically underserved areas (MUA) is challenging and not widely reported. This report seeks to characterize the outcomes of female patients with brain metastases from breast, ovarian, cervical, and endometrial cancer who underwent surgical resection in an MUA. METHODS Our institution’s electronic medical record was queried for patients who underwent a craniotomy from 2013-2022. All female patients with brain metastasis from breast, ovarian, cervical, or endometrial cancer were included. The following variables were collected: alive or deceased, survival time, demographics, past medical history, metastasis location and number, extent of resection, time to metastasis, and time to recurrence. MUA was defined by the Health Resources &amp; Services Administration’s database (data.hrsa.gov). RESULTS Nine patients had metastases from breast, four from endometrial, one from ovarian, and one from cervical cancers. Metastases were most commonly located in the posterior fossa. The median age at surgery was 65 years. The median time from primary cancer diagnosis to brain metastasis diagnosis was 2.1 years. Gross total resection (GTR) was achieved in 15/21 metastases. Recurrence occurred in 7/15 patients after a median of 10 months. At the conclusion of the study, eight patients were deceased (53%), two patients were alive with no known new metastases (13%), four were alive with new metastases (27%), and one (6.7%) was lost to follow-up. In patients who died during the study, the median survival was 9.4 months, the median age at death was 65.7 years, and 7/8 had GTR of the metastasis(es). CONCLUSION To our knowledge, this is the first report of female-specific cancer brain metastases in an MUA. The median survival time was approximately nine months, which is similar to survival reported in multi-center studies. Further studies are recommended to identify and manage cancer care disparities in MUAs.
QOL-25. IMPACTS OF IMPLEMENTING A PROSPECTIVE TREATMENT AND SURVEILLANCE PROTOCOL FOR THE MANAGEMENT OF NF2-ASSOCIATED VESTIBULAR SCHWANNOMAS ON TUMOR GROWTH, HEARING OUTCOMES, AND QUALITY OF LIFE
Authors: Julien Rousseau, Andrea Dahoud, Moujahed Labidi, Zaki El Haffaf, Marie Florescu, Issam Saliba, Marie-Hélène Gosselin, Sarah Lapointe
Journal: Neuro-Oncology (2022)

Abstract Neurofibromatosis type 2 (NF2) is an autosomal dominant neurocutaneous syndrome associated with the development of nervous system tumors, including vestibular schwannomas (VS), meningiomas, and ependymomas. Although considered a rare illness, it is a source of significant morbidity, mainly due to early hearing loss leading to decreased autonomy and productivity among young adults. Bevacizumab, a monoclonal antibody against VEGF, has been shown to improve audition and tumor size in observational studies on NF2-associated VS. The most common limitations in the literature include the lack of reliable control groups, the paucity of data on quality of life, and the lack of detailed audiology testing guidelines. Moreover, the cost of bevacizumab is a limiting factor in access to care. In our Canadian tertiary care center, bevacizumab has been offered to NF2 patients with VS complications without specific indications on optimal treatment initiation time or duration. We present a hybrid cohort study protocol with retrospective and prospective arms aimed at measuring the impacts of introducing a standardized treatment and surveillance protocol on tumor growth, hearing outcomes, and quality of life. Patients from the multidisciplinary neurofibromatosis clinic at the University of Montreal Health Center, Canada, will be evaluated for inclusion in the prospective arm through regular audiological evaluations and imaging. Eligible individuals will receive bevacizumab at an initial dose of 5 mg/kg every 2 weeks for a year while participating in serial audiological, radiological, and quality of life assessments. The results will be compared to those of our historical cohort. Our primary outcomes will be tumor growth rate (% per year) for vestibular schwannomas, meningiomas and ependymomas, audiological test results, and quality of life and subjective hearing estimated through standardized questionnaires (SF-36, SSQ). We hypothesize that patients enrolled in the prospective arm will show improved clinical response compared to our historical cohort.
NCOG-01. CLINICAL DETERMINANTS IMPACTING OVERALL SURVIVAL OF PATIENTS WITH OPERABLE BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER
Authors: Andras Piffko, Benedikt Asey, Lasse Dührsen, Inka Ristow, Johannes Salamon, Harriet Wikman, Cecile Maire, Katrin Lamszus, Manfred Westphal, Thomas Sauvigny, Malte Mohme
Journal: Neuro-Oncology (2022)

Abstract The incidence of brain metastases (BM) in non-small cell lung cancer (NSCLC) patients is continuously increasing. The recent improvements of systemic treatment in NSCLC necessitate continuous updates on prognostic subgroups and factors determining overall survival. In order to improve clinical decision-making, we investigated the clinical determinants affecting survival in patients with resectable NSCLC BM. A retrospective analysis was conducted of NSCLC patients with surgically resectable BM treated in our institution between 01/2015 and 12/2020. Relevant clinical factors affecting survival identified by univariate analysis where included in a multivariate logistic regression model. Overall, 264 patients were identified, with a mean age of 62.39 ± 9.98 years at initial diagnosis of NSCLC BM and overall survival (OS) of 23.22 ± 1.71 months. Factors that significantly affected overall survival from time of primary tumor diagnosis included the systemic metastatic load (mean: 45.9 ± 9.7 vs. 58.9 ± 9.4 months, p = 0.021) as well as a number of BM &amp;lt; 2 (mean: 25.5 ± 4.4 vs. 57.4 ± 7.8 months, p = 0.014). When adjusted for survival time after neurosurgical intervention, a significant survival benefit was found in patients &amp;lt; 60 years (32.5 ± 4.3 vs. 28.5 ± 5.2 months, p = 0.036) and patients without any concurrent systemic metastases at time of NSCLC BM diagnosis (mean 32.4 vs. 34.1, p = 0.032). Our data shows that the number of BM (singular/solitary), gender and age, but not localization (infra-/supratentorial), mass-edema index or time to BM occurrence impact overall survival in NSCLC BM patients.Additionally, our study shows that patients in prognostically favorable clinical subgroups have an overall survival, which differs significantly from current statements in literature. The described clinically relevant factors may improve the understanding of the risks and the course of this disease and aid future clinical decision making in tumor boards.
CTIM-29. PHASE 2 STUDY OF A NOVEL IMMUNOTHERAPY SL-701 IN ADULTS WITH RECURRENT GBM: IDENTIFICATION OF TREATMENT-INDUCED CD8+CD107A+ CD57+ PD-1- MEMORY T-CELLS THAT ARE ASSOCIATED WITH INCREASED SURVIVAL
Authors: David Peereboom, Ross Lindsay, Michael Badruddoja, L Burt Nabors, Priya Kumthekar, Frank Lieberman, David Tran, Surasak Phuphanich, David Schiff, Jonathan Sherman, Nicholas Butowski, Erin Dunbar, Karen Fink, Fabio Iwamoto, Christopher Moertel, Michael Schulder, Tobias Walbert, Nassir Habboubi, Krzysztof Grzegorzewski, Christopher Brooks, David A Reardon
Journal: Neuro-Oncology (2022)

Abstract Recurrent glioblastoma (GBM) is an aggressive disease with poor survival and limited treatment options. SL-701 is a novel immunotherapy comprised of synthetic peptides designed to elicit an anti-tumor immune response against GBM antigens IL-13Rα2, ephrinA2, and survivin. Here we describe an 18-color flow cytometry analysis from stage 2 of a Ph2 clinical trial of SL-701+poly-ICLC+bevacizumab (NCT02078648), in which 12-month overall survival (OS) was 50%. Of the 27 patients in stage 2, 24 (89%) developed heterogeneous T-cell responses against 1, 2, or 3 of the SL-701 CD8 peptides. Magnitude and kinetics of peptide responses were variable among these patients with no clear relationship to OS. Therefore, a phenotypic analysis of the T-cell response in all 27 patients was conducted using terraFlow, a unique data analysis approach utilizing machine learning to identify T-cell phenotypes associated with clinical response from all possible combinations of markers. In total, 10,184 unique SL-701 induced phenotypes were measured, including 223 phenotypes (P &amp;lt; 0.05) and 16 core phenotypes that uniquely represent differences between patients with OS above or below 12 months (P &amp;lt; 0.05). 50% of the core phenotypes were CD8+ CD57+ CD107a+ PD-1- SL-701-specific T-cells, which are highly-differentiated memory T-cells primed for cytotoxicity. The frequency of the CD57+ core phenotypes (8%-18%) was enhanced 1.6- to 2.3-fold in patients with an OS &amp;gt; 12 months (P &amp;lt; 0.05). Similarly, 2 core phenotypes identified cytotoxic CD4+ and CD8+ T cells, which were enhanced 1.9- and 2.5-fold in patients with an OS &amp;gt;12 months. The final 6 core phenotypes identified activated CD4+ CD154+ SL-701-specific T-cells (5%-19%) that were enhanced 0.3- to 0.5-fold in patients with an OS &amp;lt; 12 months (P &amp;lt; 0.05), suggesting helper T-cell responses in the absence of cytotoxic T-cell responses are associated with an OS &amp;lt; 12 months. Deep sequencing of SL-701-specific T-cells using whole transcriptome-based molecular cytometry is planned.
NCMP-01. CEREBRAL ANGIOSARCOMA AND DISTANT RADIATION THERAPY
Authors: Ariana Frontario, Danielle Bazer, Agnieszka Kowalska
Journal: Neuro-Oncology (2022)

Abstract Angiosarcoma is a rare malignant tumor originating from vascular endothelial cells. Typically, the diagnosis of angiosarcomas carry poor prognosis. Radiation exposure is one of the most common risk factors for angiosarcomas. Due to the rarity of angiosarcoma, there is sparse literature, hence it is mostly seen in case reports. We describe a case of cerebral angiosarcoma with an unknown primary malignancy in a patient with distant history of non-Hodgkin’s lymphoma treated with chemotherapy and radiation therapy to the thorax. A 54 year old male with a history of Non-Hodgkin’s Lymphoma was treated with ABVD chemotherapy and thoracic radiation therapy in 1995,presented for bilateral vision loss. Neurologic examination revealed a left homonymous hemianopia .Further investigation with brain Magnetic Resonance Imaging revealed hemorrhagic lesions in the bilateral frontal and in the right parietal-occipital lobes. Computed tomography of the chest, abdomen, and pelvis was negative for malignancy. The patient underwent a right occipital craniotomy with resection of right parietal occipital lesion. Histopathology revealed metastatic angiosarcoma. It has been acknowledged that exposure to external beam radiotherapy puts patients at risk for angiosarcoma in the future. It is believed that radiation may induce the development of AS by several mechanisms. One mechanism is the direct oncogenic effect of ionizing radiation, which can damage DNA, leading to genome instability and mutation of cancer-related genes. A prior literature review noted twenty cases of angiosarcoma developing following therapeutic irradiation. Our particular patient’s prior exposure to irridation did not include a brain radiation field, so it is unlikely this patient had radiation induced angiosarcoma.Furthermore, it does not appear that his prior radiation exposure explains the location of his angiosarcoma as his radiation field was localized to chest. Although angiosarcoma is rare, it deserves further investigation to increase the knowledge base on etiology of metastasis.
PATH-34. SOLITARY FIBROUS TUMOR: NATURAL HISTORY AND PROGNOSIS IN ACCORDANCE WITH THE WHO 2021 CLASSIFICATION OF CNS TUMORS
Authors: Kathryn Eschbacher, Sarah Jenkins, Karen Fritchie, Evgeny Moskalev, Alissa Caron, Michael Link, Paul Brown, Andrew Guajardo, Daniel Brat, Ashely Wu, Sandro Santagata, David Louis, Priscilla Brastianos, Alexander Kaplan, Brian Alexander, Sabrina Rossi, Fabio Ferrarese, David Raleigh, Minh Nguyen, John Gross, Jose Velazquez Vega, Fausto Rodriguez, Arie Perry, Maria Martinez-Lage Alverez, Florian Haller, Caterina Giannini
Journal: Neuro-Oncology (2022)

Abstract Meningeal solitary fibrous tumor (SFT) is a rare tumor with high propensity to recur and metastasize, even late in the course of disease. The WHO 2021 classification of CNS tumors divides SFT in 3 grades, based on mitotic index and necrosis. We re-examined our cohort of 126 patients (57 F, 69 M; mean age 53.0 years) with SFT, confirmed by STAT6 nuclear positivity and/or NAB2::STAT6 fusion, with extended follow-up (median 7.6 years; range 4 days-26.6 years). Tumors included 76 grade 1, 36 grade 2 and 14 grade 3 according to 2021 WHO criteria, evaluated at primary resection (n=90), recurrence (n=35), or metastasis (n=1). Fifty-six patients had one or more post-surgical events, the earliest event being local recurrence (n=41) or metastasis (n=15). Forty patients died (29 of disease; 9 of other causes; 2 unknown). Overall survival (OS), and progression-free survival (PFS, recurrence and/or metastasis) from time of primary resection (n=90) were not significantly associated with grade; however, risk of metastasis differed significantly (5-year estimates: 4.1%, 15.3%, and 37.8% for grades 1, 2, and 3 SFT, respectively; p=0.005). NAB2::STAT6 fusion status was known in 101 cases (51 = ex5-7-ex16-17, 26 = ex4_ex2-3; 12 = ex2-3_exANY/other and 12 =no fusion). Disease specific 5-year survival in primary tumors with molecular data (n = 75) was 80.0% in patients whose tumors harbored ex5-7_ex16-17 compared to 93.3% in all others combined (p=0.014). Targeted TERT promoter mutation testing was performed in 98 patients, revealing patients with tumors lacking TERT promoter mutation (n = 88) were younger at time of surgery than those harboring a mutation (n=10; p = 0.022), and none with a mutation harboring concurrent ex5-7_ex16-17 fusion (p = 0.0009). In summary, WHO 2021 grade is associated with risk of metastasis. Patients whose tumors harbor ex5-7_ex16-17 fusion have a higher risk of dying from the disease.